SETDB2 and RIOX2 are differentially expressed among renal cell tumor subtypes, associating with prognosis and metastization

Abstract

Increasing detection of small renal masses by imaging techniques entails the need for accurate discrimination between benign and malignant renal cell tumors (RCTs) as well as among malignant RCTs, owing to differential risk of progression through metastization. Although histone methylation has been implicated in renal tumorigenesis, its potential as biomarker for renal cell carcinoma (RCC) progression remains largely unexplored. Thus, we aimed to characterize the differential expression of histone methyltransferases (HMTs) and histone demethylases (HDMs) in RCTs to assess their potential as metastasis biomarkers. We found that SETDB2 and RIOX2 (encoding for an HMT and an HDM, respectively) expression levels was significantly altered in RCTs; these genes were further selected for validation by quantitative RT-PCR in 160 RCTs. Moreover, SETDB2, RIOX2, and three genes encoding for enzymes involved in histone methylation (NO66, SETD3, and SMYD2), previously reported by our group, were quantified (RT-PCR) in an independent series of 62 clear cell renal cell carcinoma (ccRCC) to assess its potential role in ccRCC metastasis development. Additional validation was performed using TCGA dataset. SETDB2 and RIOX2 transcripts were overexpressed in RCTs compared to renal normal tissues (RNTs) and in oncocytomas vs. RCCs, with ccRCC and papillary renal cell carcinoma (pRCC) displaying the lowest levels. Low SETDB2 expression levels and higher stage independently predicted shorter disease-free survival. In our 62 ccRCC cohort, significantly higher RIOX2, but not SETDB2, expression levels were depicted in cases that developed metastasis during follow-up. These findings were not apparent in TCGA dataset. We concluded that SETDB2 and RIOX2 might be involved in renal tumorigenesis and RCC progression, especially in metastatic spread. Moreover, SETDB2 expression levels might independently discriminate among RCC subgroups with distinct outcome, whereas higher RIOX2 transcript levels might identify ccRCC cases with more propensity to endure metastatic dissemination.

Targeting the Immune system and Epigenetic Landscape of Urological Tumors

“…Indeed, inactivation of this histone-modifying enzyme results in increased tumor progression and aggressiveness, and poorer patient outcome [93]. To illustrate the different epigenetic background in the heterogeneity of RCC, a set of histone methyltransferases and demethylases is able to accurately discriminate among the various RCC subtypes and oncocytoma, an important differential diagnosis [94]. Also, several promoter-methylated genes involved in the various hallmarks of cancer are found in RCC, including the ones related to angiogenesis (in which VHL is included), metabolism, apoptosis and cell cycle, among others [95].…”

<p>Oncogenic Roles Of A Histone Methyltransferase SETDB2 In AML1-ETO Positive AML</p>

“…The expression of SETDB2 in CD34+/CD38cells isolated from AML1-ETO positive cases (n = 10) was significantly higher than that in healthy human CD34 +/CD38 cells ( Figure 1A). In addition, SETDB2 expression in t(8;21) positive AML was significantly higher than that in normal bone marrow CD34+ cells, PML-RARa, inv (16) and FLT3-ITD positive AML cases ( Figure 1B). In the AML cell lines, we also found that SETDB2 expression was significantly higher in t(8;21) positive AML cells than in other t(8;21) negative AML cells ( Figure 1C).…”

“…The CD34+CD38cells were used to detect the expression of SETDB2. The second sample cohort included bone marrow tissue of 13 normal healthy individuals and 96 AML patients collected from June 2017 to June 2018 (including t(8; 21), n = 56; pML-RARa, n = 25; inv (16), n = 15), used to isolate mononuclear cells for detection of SETDB2 expression; the third sample cohort included 42 patients with AML1-ETO negative and 50 patients with AML1-ETO positive AML from June 2013 to June 2018. These cases contain patient survival data.…”

“…Previous studies have shown that SETDB2 is an oncogene in gastric and renal cancer. 16,17 SETDB2 plays a role in promoting the development of renal cancer by transcriptional inhibition of WW domain-containing oxidoreductase Figure 5 SETDB2 knockdown increases sensitivity to epigenetic inhibitors. Notes: Dose-response curves are shown for control or SETDB2 shRNA-treated SKNO-1 and Kasumi-1 cells cultured in increasing concentrations of JQ1 (A) and C646 (B).…”

Expression of microRNA-99a-3p in Prostate Cancer Based on Bioinformatics Data and Meta-Analysis of a Literature Review of 965 Cases

“…The Cancer Genome Atlas (TCGA) ( http://cancergenome.nih.gov/ ) is a database of expression profiles for at least 30 kinds of cancers, including prostate cancer [ 25 – 27 ]. TCGA can be used to explore clinicopathological parameters associated with patients with cancer, which were used in this study [ 28 , 29 ]. In the current study, the RNA sequencing (RNA-Seq) data for prostate cancer patients, which were taken from the Illumina MiSeq RNA-Seq platform, contained 498 prostate cancer cases and 52 normal prostate cases, up to 1st November 2017.…”